calcineurin inhibitor

**Drugs** - Cyclosporine (binds cyclophilin). - Tacrolimus (FK506; binds FK-binding protein, FKBP12). It is about 10-100x more potent than cyclosporine. - Topical forms: tacrolimus and pimecrolimus, used for atopic dermatitis.

**Mechanism** 1. The drug binds an intracellular immunophilin (cyclophilin for cyclosporine, FKBP for tacrolimus). 2. The drug-immunophilin complex binds and inhibits calcineurin (also called protein phosphatase 2B), a Ca2+/calmodulin-dependent serine/threonine phosphatase. 3. Calcineurin can no longer dephosphorylate NFAT (nuclear factor of activated T cells). 4. NFAT cannot translocate to the nucleus, so IL-2 and other cytokine genes are not transcribed. 5. T-cell activation and proliferation fall, especially CD4+ helper T cells.

Contrast with sirolimus (rapamycin) and everolimus. These also bind FKBP, but the complex inhibits mTOR, which blocks the response to IL-2 and so arrests the cell cycle at G1→S. Sirolimus is not nephrotoxic, but it causes hyperlipidemia, impaired wound healing, and pancytopenia.

**Clinical uses** - Prophylaxis of solid organ transplant rejection (kidney, liver, heart, lung) and GVHD prophylaxis after hematopoietic stem cell transplant. - Autoimmune disease: psoriasis, rheumatoid arthritis, atopic dermatitis, severe ulcerative colitis (rescue therapy), lupus nephritis (voclosporin), nephrotic syndrome, and uveitis.

**Adverse effects (high-yield)** - **Nephrotoxicity**: the most important toxicity. It results from afferent arteriolar vasoconstriction, which lowers GFR, and it can cause chronic interstitial fibrosis. It is dose-dependent and reversible early on. - **Hypertension** - **Hyperkalemia** and **hypomagnesemia** - **Neurotoxicity**: tremor, headache, seizures, PRES - **Hyperglycemia/new-onset diabetes**: more with tacrolimus (pancreatic β-cell toxicity) - **Cyclosporine-specific**: gingival hyperplasia, hirsutism, hyperlipidemia - **Tacrolimus-specific**: alopecia, more neurotoxicity, and more post-transplant diabetes - Increased risk of infection (CMV, fungal, and others) and malignancy (skin cancer, lymphoma/PTLD) - Thrombotic microangiopathy/HUS (rare)

**Pharmacokinetics and interactions** - Both are metabolized by **CYP3A4** and are substrates of P-glycoprotein. They have a narrow therapeutic index, so trough levels are monitored. - CYP3A4 inhibitors raise levels and increase toxicity. Examples are azole antifungals, macrolides (erythromycin, clarithromycin), diltiazem/verapamil, and grapefruit juice. - CYP3A4 inducers lower levels and risk rejection. Examples are rifampin, phenytoin, carbamazepine, phenobarbital, and St. John's wort. - Combining them with other nephrotoxic drugs (NSAIDs, aminoglycosides, amphotericin B) worsens kidney injury. - Combining them with K-sparing diuretics, ACE inhibitors, or ARBs increases the risk of hyperkalemia.

**Exam pearls** - "Transplant patient with tremor, hypertension, rising creatinine, and hyperkalemia" suggests calcineurin inhibitor toxicity. - Tacrolimus is favored in liver and kidney transplant for lower rejection rates. Cyclosporine is more associated with gingival hyperplasia and hirsutism. - Mnemonic: "Cyclosporine = Cyclophilin, gum overgrowth (Cyclo-gums), hair growth." Both drugs are associated with the "Nephrotoxic, Neurotoxic, Hypertension, Hyperglycemia" group.